Diethyl Ether → HCID 86703993, compound

HRID 1773913Notes

Reaction equation

HRID 1773913 reaction equation
I[C:2]1N2[C:5]([CH:6]([O:16][CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)[C:7]3[CH:15]=[CH:14][CH:13]=[CH:12][C:8]=3[CH2:9][CH2:10]2)=[N:4][C:3]=1I.[CH3:25][CH2:26][Mg+].[Br-].CCO[CH2:32][CH3:33].[C:34](N=C=O)([CH3:37])([CH3:36])[CH3:35].[NH4+:41].[Cl-].[NH4+:43].[OH-:44].[CH2:45](Cl)Cl>C1COCC1>[CH2:35]([NH:41][C:2]([C:3]1[N:4]=[C:5]2[N:43]([CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH:6]2[O:16][CH:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)[C:26]=1[CH3:25])=[O:44])[C:34]1[CH:37]=[CH:33][CH:32]=[CH:45][CH:36]=1

Participants

9

Reactant 7

HCID 3283Diethyl EtherHCID 6344DichloromethaneHCID 14923Ammonium HydroxideHCID 25517Ammonium ChlorideHCID 62412tert-Butyl isocyanateHCID 86703994HCID 86703994, compoundHCID 178461630HCID 178461630, compound

Product 1

HCID 86703993HCID 86703993, compound

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 1,2-diiodo-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene (example 219) (437 mg, 1 mmole) in CH2Cl2 (4 mL) and THF (1 mL) at 0° C. is added EtMgBr 3M solution in Et2O (1 mL, 3 mmoles). The ice bath is removed and the reaction mixture is stirred at room temperature for 90 minutes. Tert-butylisocyanate (618 μL, 5 mmoles) is added to the above solution. The reaction mixture is stirred at room temperature for 3 hours. A (1:1) solution of saturated aqueous NH4Cl and concentrated NH4OH is added and the aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over MgSO4, filtered and the solvent removed under reduced pressure. The residue is purified by silica gel chromatography eluting with (CH2Cl2:MeOH:NH4OH) (98:2:0.2) to (95:5:0.5). The residue is triturated in iPr2O to afford 1-methyl-4-(1-methylpiperidin-4-yloxy)-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene-2-carboxylic acid benzylamide melting at 161° C.

Workup

  1. customThe ice bath is removed
  2. stirringThe reaction mixture is stirred at room temperature for 3 hours
  3. extractionthe aqueous phase is extracted three times with CH2Cl2
  4. dry with materialThe organic phase is dried over MgSO4
  5. filtrationfiltered
  6. customthe solvent removed under reduced pressure
  7. customThe residue is purified by silica gel chromatography
  8. washeluting with (CH2Cl2:MeOH:NH4OH) (98:2:0.2) to (95:5:0.5)
  9. customThe residue is triturated in iPr2O

Sources & evidence

ORD record
ord-fbae7bb2738c4ab89ec8cd59456d8636
Source dataset
uspto-grants-2016_02
Patent number
US09255101B2

Reaction notes

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